9-72821066-AT-TA

Variant names:

• chr9-72821066-AT-TA
• NM_138691.3:c.1988_1989delATinsTA
• TMC1 p.Asp663Val

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_138691.3(TMC1):​c.1988_1989delATinsTA​(p.Asp663Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D663G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

TMC1 (HGNC:16513): (transmembrane channel like 1) This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]

TMC1 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_138691.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.85843 (below the threshold of 3.09). Trascript score misZ: 1.5687 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 7, nonsyndromic genetic hearing loss, autosomal dominant nonsyndromic hearing loss 36, hearing loss, autosomal recessive, autosomal dominant nonsyndromic hearing loss.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138691.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	NM_138691.3	MANE Select	c.1988_1989delATinsTA	p.Asp663Val	missense	N/A	NP_619636.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	ENST00000297784.10	TSL:1 MANE Select	c.1988_1989delATinsTA	p.Asp663Val	missense	N/A	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000340019.4	TSL:5	c.1988_1989delATinsTA	p.Asp663Val	missense	N/A	ENSP00000341433.3	Q8TDI8
	TMC1	ENST00000645208.2		c.1988_1989delATinsTA	p.Asp663Val	missense	N/A	ENSP00000494684.1	Q8TDI8

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-75435982;